Adaptation of Cryptococcus neoformans to Mammalian Hosts: Integrated Regulation of Metabolism and Virulence

Abstract

The basidiomycete fungus Cryptococcus neoformans infects humans via inhalation of desiccated yeast cells or spores from the environment. In the absence of effective immune containment, the initial pulmonary infection often spreads to the central nervous system to result in meningoencephalitis. The fungus must therefore make the transition from the environment to different mammalian niches that include the intracellular locale of phagocytic cells and extracellular sites in the lung, bloodstream, and central nervous system. Recent studies provide insights into mechanisms of adaptation during this transition that include the expression of antiphagocytic functions, the remodeling of central carbon metabolism, the expression of specific nutrient acquisition systems, and the response to hypoxia. Specific transcription factors regulate these functions as well as the expression of one or more of the major known virulence factors of C. neoformans. Therefore, virulence factor expression is to a large extent embedded in the regulation of a variety of functions needed for growth in mammalian hosts. In this regard, the complex integration of these processes is reminiscent of the master regulators of virulence in bacterial pathogens.

Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

“…The small capsule size could also be indirectly due to metabolic changes in carbon and nitrogen metabolism, reduced synthesis and/or trafficking of capsule material, and/or changes in the cell wall structure leading to inefficient capsule attachment (28,39,53). Although many factors regulate capsule elaboration, it is known that a defect in acetylation of the polysaccharide can influence capsule size, and it is possible that reduced acetyl-CoA levels due to a block in ␤-oxidation may reduce acetylation (28,35).…”

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

“…Previous studies of C. neoformans virulence factors have implied that Cu plays important, but poorly characterized, roles in fungal virulence. This hypothesis is supported by the Cu dependence of many biological processes and virulence-related proteins, including melanin biogenesis, superoxide dismutase activity and Fe uptake through Cu-dependent ferroxidase activity [12][13][14][15] . However, recent studies also demonstrated that the Cu-detoxification proteins known as MTs are essential for fungal survival during pulmonary colonization and for virulence, indicating that C. neoformans encounters elevated Cu levels in the host early in the infectious process 5 .…”

Defects in Phosphate Acquisition and Storage Influence Virulence of Cryptococcus neoformans

“…Alveolar macrophages in the lungs are the first line of immune defense after infection. However, C. neoformans is known to persist in the intracellular environment and resist the unfavorable conditions of the phagolysosome (e.g., acidic pH, degradative enzymes, and nutrient limitation) (6,7). C. neoformans is also known to modulate the immune response with the production of capsule and prostaglandins (8).…”